Cyanidin Chloride Improves LPS-Induced Depression-Like Behavior in Mice by Ameliorating Hippocampal Inflammation and Excitotoxicity

Depression is a global disease that places a significant burden on human health. Neuroinflammation and disturbance of glutamate metabolism in brain regions, such as the hippocampus, play vital roles in the development of depression. Previous studies have shown that cyanidin chloride (Cycl) has anti-inflammatory and antioxidant properties with neuroprotective effects in peripheral tissues. However, the effects of Cycl on depression and the possible mechanism by which this compound targets brain regions remain less elucidated. We investigated the role of Cycl in lipopolysaccharide (LPS)-induced depression and examined the influence of the drug on central inflammation and the expression of excitatory amino acid transporters in the hippocampus. We found that prophylactic i.p. application of Cycl at 20 or 40 mg/kg for 5 days significantly reduced the immobility time assessed by the tail suspension test (TST) and forced swim test (FST) in LPS-challenged mice, suggesting an effective antidepressant activity of the drug. Western blotting and immunofluorescence staining in the hippocampus revealed that Cycl inhibited the upregulation of proinflammatory cytokines, including TNF-alpha and IL-6, and suppressed the hyperactivity of microglia induced by LPS, indicating an anti-inflammatory role in the hippocampus. Moreover, treatment with Cycl also recovered the downregulated expression of glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), and glutamate-aspartate transporter (GLAST) and excitatory amino acid transporter 2 (EAAT2), two members in the excitatory amino acid transporter family. The role of Cycl was also verified in cultured BV2 and U251 cells. In conclusion, the present in vivo and in vitro studies demonstrate that Cycl exerts potent antidepressant action in an LPS-induced depression model and the underlying mechanism is associated with reduced hippocampal inflammation, improved function, and attenuated induced